Cell surface peptide/MHC complexes are ligands for T cell receptors (TcR) on CD8+ and CD4+ T lymphocytes. Our research is aimed toward understanding the biochemical and functional details of MHC-peptide and [MHC/peptide]-TcR interactions; these characterizations underlie a fundamental understanding of immune responses and the rational development of peptide-based immunotherapies. An emerging model of immune recognition maintains that the ability of TcR to engage dissimilar epitopes in a cross -reactive manner plays an important role in T cell development and peripheral function. We are currently studying how the TcR of a murine CTL clone recognizes two different peptide/MHC class I complexes. This CTL was originally isolated as a xenoreactive clone specific for the human class I molecule HLA-A2.1 complexed with an endogenous human peptide. Since thymic selection theory maintains that T cells are positively-selected on self MHC/peptide complexes, we reasoned that this murine CTL should be capable as well of recognizing some self (murine) class I molecule + peptide complex. We were able to identify a synthetic peptide which forms a complex with H-2 Db that is also recognized by this CTL clone. Analog peptides were used extensively to probe TcR epitope recognition in this system. Our findings suggest that the TcR of this CTL clone "sees" these two epitopes in a non-identical manner, making both shared and complex-specific contacts with each peptide/class I combination. In a collaboration under way, we hope to obtain x-ray crystal structures of these two complexes and gain further structural insights into their topologies. The functional consequences of epitope degeneracy are being studied in the context of CTL response made in melanoma patients to HLA-A2.1 complexed with a peptide derived from the melanoma/melanocyte protein MART-1. The recently-completed initial phase of this work provides evidence in support of our hypothesis that the high regularity of observed responses to this epitope may be due in part to T cell encounters with epitope mimics of the MART-1 peptide. The primary sequence of the MART peptide contains a hydrophobic motif that occurs frequently among a variety of functionally unrelated proteins, and many such MART-1-like sequences were identified that serve as cognate peptides for patient-derived CTL. We are currently beginning to study how mimicry might be influencing the efficacy of this anti-tumor CTL response.